Mesenchymal stem cells (MSCs) are currently being evaluated in over 180 open clinical trials for the treatment of a variety of human diseases. Despite the growing use of MSCs in clinical therapy, many MSC-based clinical trials have failed to meet their primary endpoint of efficacy and patient outcomes have been poorly predicted based on cell potency studies conducted in vitro or in experimental animal models. Indeed, lack of knowledge regarding the functional complexity of MSC populations, pathways that specify cellular behaviors that contribute to cell potency, and species differences in these pathways represent a major impediment toward developing optimized and predictable clinical therapies. To overcome these limitations, this proposal will compare and contrast species differences in the basic biology of rodent and human MSCs, determine how different biological functions that affect cell potency are specified within populations, and demonstrate a functional link between pathways that regulate basic cell biology and non-progenitor functions. To enhance the value of pre-clinical animal models, this laboratory will also create a repository of MSCs from different inbred, transgenic, and knockout strains of mice and supply these cells to the greater scientific community. Methods used to produce cells yield non-immortalized, non-clonal populations that recapitulate the functional complexity and behavior of human MSCs. Consequently, their use provides a means to standardize biological and translational studies across laboratories and between different experimental animal models, thereby augmenting the value, of rodent models for predicting cellular behaviors in the clinical arena.